Combination for the treatment of alcohol and drug dependence containing an opioid antagonist and a NMDA receptor complex modulator

ABSTRACT

A pharmaceutical composition for the treatment of alcohol and drug dependence, comprising a therapeutically effective amount of a combination of: (i) an opioid antagonist; and (ii) a NMDA receptor complex modulator. A pharmaceutical kit is also provided, comprising these two substances. The opioid antagonist can, for example, be naltrexone and the NMDA receptor complex modulator can be a spermidine site modulator such as acamprosate.

The present invention relates to a method for the treatment of alcoholand drug dependence.

More specifically the present invention relates to a method for thetreatment of the alcohol dependence.

It relates also to a method for the treatment of a dependence to drugssuch as opioid derivatives, cannabinoides, nicotin derivatives,amphetamines and tranquilizers.

The present invention also relates to compositions and kits for suchtreatment.

A number of studies indicated a relationship between alcohol intake andendogenous opioid activity (Schulz R., Wuster M., Duka T., Herz A.,Acute and chronic ethanol treatment changes endorphin levels in brainand pituitary, Psychopharmacology, 68, 221-227, 1980; Hoffman P.,Melchior C., Ritzmann R. F., Tabakoff B., Structural requirements forneurohypophyseal peptide effects of ethanol tolerance, Alcohol Exp.Clin. Res., 5, 154, 1981). Ethanol intake increases synthesis andrelease of beta endorphin in the pituitary gland and the stimulation ofopiate receptors seems to be weakly involved in the regulation ofpositive reinforcement properties of ethanol. These findings havesuggested the use of opiates antagonists (such as naloxone ornaltrexone) to prevent ethanol-induced analgesia, intoxication, coma(Kiianmaa K., Tabakoff B. Neurochemical correlates of tolerance andstrain differences in the neurochemical effects of ethanol, Pharm.Biochem. Behav., 18, 383-388, 1983) or more recently ethanol dependence(Davidson D., Amit Z., Naltrexone blocks acquisition of voluntrayethanol intake in rats, Alcohol Clin. Exp. Res., 21, 677-683, 1997).Naltrexone, when used together with supportive therapy, has been shownto reduce the rate of relapse to heavy drinking in alcohol dependentpatients (O'Malley S. S., Opioid antagonists in the treatment of alcoholdependence: clinical efficacy and prevention of relapse, AlcoholAlcoholism 31, 77-91, 1996).

The present invention provides a method for the treatment of alcohol anddrug dependence comprising administering to a patient a therapeuticallyeffective amount of a combination of: (i) an opioid antagonist, such asnaltrexone or naloxone; and (ii) a NMDA receptor complex modulator, inparticular a spermidine site modulator. The present invention is alsodirected to compositions and pharmaceutical kits containing the same.Such combination therapy provides surprisingly efficient and effectivemethodology for use in the treatment of alcohol and drug dependence.

The NMDA subtype of the glutamate receptor is a ligand-gated ion channelinvolved in excitatory neurotransmission in the mammalian CNS.Activation of the NMDA receptor-channel complex has been implicated inseveral physiological phenomena important to higher order CNS functions.Overstimulation of this receptor results in an inflow of Ca⁺⁺ andneuronal excititoxicity. This ligand-gated ionotropic glutamate receptoris subject to complex regulation by a number of ligands. Separateregulatory sites include the binding site for the agonist I-glutamate; ahigh affinity binding site for the obligatory co-agonist glycine; a sitewhere Zn⁺⁺ acts to allosterically inhibit the agonist-induced responseindependently of membrane potential; a site within the channel whereMg⁺⁺ and phencyclidine (PCP), dizocilpine and ketamine bind to produce avoltage-dependent open channel block; and a distinct binding site forthe endogenous polyamines, spermine and spermidine, which modulate NMDAreceptor function (Bergeron et al., J. Med. Chem., 39, 5257, 1996).

Spermidine can modulate certain NMDA receptor subtypes by eitherglycine-independent or glycine dependent mechanisms (or both). Thisaction of polyamines to potentiate agonist-mediated responses may residein its shielding of the NMDA receptor proton sensor from theextracellular pH. The influence of polyamines in vivo will depend oneffective extracellular levels and the presence of suitable polyaminesensitive NMDA receptors sub-units. These in vivo effects of polyamineson NMDA receptor may explain the excessive activation of NMDA receptorsobserved during some pathological situations in which polyaminesynthesis is not preserved.

Acamprosate is an example of a compound which is able to induce amodulation of the NMDA receptor complex by interactions on a spermidinesensitive site.

Other examples of compounds which induce a modulation of the NMDAreceptor complex are:

glycine antagonists such as L 701 324 (J. Kotlinska et al.,Psychopharmacology, 127, 238, 1886);

ibogaine: (Popick P. et al., J. Pharmacol. Exp. Ther., 275, 753, 1995),

memantine and derivatives: (Popick P. et al., Pharmacol. Biochem.Behav., 53, 791, 1996),

ifenprodil and eliprodil: (Schoemaker II. et al., Eur. J. Pharmacol.,176, 240, 1990),

modulators of the NMDA receptor complex on the glycine site (BienkowskiP., Alcohol, 15, 87, 1998).

By “administering a combination”, or the like, when referring tocomponent (i), and component (ii), of the present invention, it is meantthat the components are administered concurrently to a patient beingtreated. By concurrently, it is meant that each component may beadministered at the same time or sequentially in any order at differentpoints in time. However if not administered at the same time, theyshould be administered sufficiently closely in time so as to provide thedesired treatment effect. Suitable dosing intervals and dosing orderwith such compounds will be readily apparent to those skilled in theart, once armed with the present disclosure. Preferably, all componentsare administered at the same time, and if not administered at the sametime, preferably they are all administered less than one hour apart fromone another.

The present invention also includes pharmaceutical compositionscomprising or consisting essentially of, in combination, an opioidantagonist (such as naltrexone), and a NMDA receptor complex modulator.Such compositions may be in solid, liquid, transdermal, transnasal, ordepot dosage units and may further include a suitable pharmaceuticalcarrier. Examples of compositions for the oral route are coated tabletsand capsules.

The present invention also includes pharmaceutical kits comprising orconsisting essentially of an opioid antagonist (such as naltrexone),together with a NMDA receptor complex modulator. In the kit, the opioidantagonist and the NMDA receptor complex modulator may each be presentedin separate vials as compounds, and/or in separate vials as compounds incombination with a pharmaceutically acceptable carrier. Alternatively,the opioid antagonist and the NMDA receptor complex modulator may becombined together in one or more vials, with or without a carrier. Thus,for example, the invention includes pharmaceutical kits comprising aseparate vial comprising the opioid antagonist and a separate vialcomprising the NMDA receptor complex modulator, each vial alsocontaining, if desired, a carrier.

The compositions and kits of the present invention may be employed inthe treatment of alcohol and drug dependence.

For use in the treatment of diseases characterized by abnormally highconsumption of alcohol, a daily dosage of active ingredients can beabout 0.5 to 20 mg/kg of body weight for the opioid antagonist such asnaltrexone and about 10 to 400 mg/kg of body weight for a NMDA receptorcomplex modulator such as acamprosate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the alcohol intake in a first series of testsin rats.

The unexpected effect of the combinations is shown in the followingtests.

Material and Methods

Ethanol dependent rats were selected as previously described (BoismareF., Daoust M., Moore N., Saligaut C., Chadelaud M., Chrétien P., DurlachJ., Lhuintre J. P., A homotaurine derivative reduces the voluntaryintake of ethanol by rats: are cerebral GABA receptors involved?, Pharm.Biochem. Behav., 21, 787-789, 1984).

Alcoholization

Adult male Long Evans rats weighing 180±20 g at the beginning of theexperiment were obtained from “Centre d'élevage Janvier” (France). Therats were housed in individual cages and had free access to food (UAR,France standard diet). They were kept with an ambient temperature of 21°C. and a 12 hr/12 hr light-dark photoperiod. During the initialselection period (14 days), they only had access to a 10% (v/v) ethanolsolution, prepared from 95% ethanol and water as drinking fluid for 14days. This period was followed by another two-week period during whichthey has a free choice between ethanol solution and water. The twofluids three bottles method was used to prevent fluid selection on thebasis of bottle situation. Every other day, fluid intakes and bodyweights were measured, the drinking bottles were refilled and randomlyrotated. Food consumption was also measured each week be weighting foodpellets. Animals preferring ethanol 4-5 g/kg per day during these lasttwo seeks (≈30% of the rats) were selected as drinking rats and used forthe different treatments.

Treatments

All the drugs were prepared as saline (NaCl 0.9%) solutions and animalswere daily i.p. injected with: acamprosate 100 mg/kg, naltrexone 10mg/kg, acamprosate 100 mg/kg+naltrexone 10 mg/kg or saline 1 ml/200 gbody weight. Five groups of six or seven alcohol preferring rats wereused. Each group receiving its own treatment. Rats were treated for 14days (treatment period) and after that, they were kept one week morewithout treatment for the post-treatment analysis. Alcohol intakes wereexpressed as gram of absolute alcohol drunk per kilo of body weight perday (g.kg.d) for alcohol.

Results

Body weights and ethanol consumption were the same in both groups duringthe pre-treatment period (p<0.1).

Ethanol intake significantly decreased in acamprosate (p<0.008) andnaltrexone (p=0.092) groups. Acamprosate and naltrexone when are giventogether, present a significant effect on ethanol intake (p<0.001).

The results are shown in FIG. 1.

FIG. 1 represents means±sem of ethanol intake, expressed as gram ofabsolute alcohol during each period of pre-treatment, treatment andpost-treatment in all groups of rats. 6 or 7 rats per group for: Control(Cont), Acamprosate 100 mg/kg/d (AC), Naltrexone 10 mg/kg/d (NTX),Acamprosate 100 mg/kg/d+Naltrexone 10 mg/kg/d (AC+NTX).

The most interesting finding is that the acamprosate and naltrexone havean unexpected effect on alcohol intake when they are administeredtogether.

EXAMPLES OF PHARMACEUTICAL COMPOSITIONS Example 1 Tablet

A tablet is prepared with the following composition (mg/tablet):

core: acamprosate 350 naltrexone  25 to 50 microcristalline cellulose 25 to 75 (for example 50) PVP 30  10 to 25 (for example 15)croscarmellose  10 to 20 (for example 17) external phase: croscarmellose 10-20 (for example 17) microcristalline cellulose  25-75 (for example50) lactose  75-125 (for example 100) magnesium stearate  9-15 (forexample 12) anhydrous colloidal silica  1-3 (for example 2) coating:sepifilm (HPMC, TiO₂, stearic acid)  25-45 (for example 30).

The core of this tablet is obtained by wet granulation.

Example 2 Capsule with Immediate Release

The capsule has the following composition (mg/capsule):

acamprosate 350 naltrexone  25 gelucire (polyglycosyl glyceride) 250-330(for example 290) soya bean lecithine  1-10 (for example 7) sorbitannetrioleate  10-35 (for example 35).

Example 3 Capsule with Extended Release

The capsule has the following composition (mg/capsule):

acamprosate 350 naltrexone  25 gelucire (polyglycosyl glyceride) 200-300(for example 250) soya bean lecithine  1-10 (for example 7) sorbitannetrioleate  10-50 (for example 35) precirol (glycerol stearate)  20-60(for example 40).

What is claimed is:
 1. A pharmaceutical composition for the treatment ofalcohol and drug dependence comprising a therapeutically effectiveamount of a combination of: (i) an opioid antagonist which is eithernaloxone or naltrexone; and m (ii) a NMDA receptor complex modulatorwhich is acamprosate.
 2. A pharmaceutical composition as claimed inclaim 1 in which said opioid antagonist is naltrexone.
 3. Apharmaceutical kit comprising: (i) an opioid antagonist which is eithernaloxone or naltrexone; and (ii) a NMDA receptor complex modulator whichis acamprosate.
 4. A pharmaceutical kit as claimed in claim 3 in whichsaid opioid antagonist is naltrexone.